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Arsenic’s cancer paradox resolved

By Robert Adler

A surprising new genetic mechanism may explain arsenic’s paradoxical ability to cause some cancers and cure others. Researchers say the discovery may lead to improved treatments for some kinds of leukemia, and supports the need for strict limits on environmental arsenic exposure.

Chi Dang and Wen-Chien Chou at Johns Hopkins University School of Medicine, in Maryland, noticed that arsenic caused certain kinds of cancer cells to puff up and die. They found many chromosomes in these cells were fused end-to-end.

This implicated telomerase, an enzyme that keeps the end parts of chromosomes, called telomeres, intact. “Once we saw the fused chromosomes, we knew that telomerase might be responsible,” says Dang.

The researchers found that arsenic suppresses the hTERT gene, which codes for one of the two building blocks of telomerase. They further showed that reduced telomerase shortened telomeres in dividing cells, causing frequent end-to-end chromosomal tangles.

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The researchers think the accumulation of these genetic mix-ups killed the cells. “Cancer cells are normally deficient in telomerase, and they rearrange their genetic material to their advantage,” says Dang. “The arsenic shuffles it some more, just enough to make them commit suicide and die.”

Brink of catastrophe

Calvin Harley, Chief Scientific Officer at Geron Corporation, in Menlo Park, California, agrees. “Cancer cells are basically on the brink of telomere catastrophe. So any inhibition of telomerase can lead to cell death.” In the last decade, researchers in China, Europe and the United States found that the compound arsenic trioxide was dramatically effective against acute promyelocytic leukemia (APL) that had become resistant to other chemotherapy.

Many researchers have worked to clarify arsenic’s ability to kill APL cells quickly, but the new findings imply a new mechanism. “I find this intriguing,” says Martin Privalsky, a molecular biologist at the University of California, Davis. “It suggests an additional, previously unknown, longer term effect.”

Like Dang, Privalsky thinks the new findings may also clarify the cancer-causing effect of arsenic. “That’s been a mystery for a long time,” he says. “Environmental doses are very small, but over a long time the accumulation of chromosomal abnormalities could be important.”